Triptolide (TPL) is an abietane diterpene lactone compound with a unique configuration containing 3 epoxy groups and an α, β-unsaturated five-membered lactone ring structure, which is isolated from Tripterygium wilfordii Hook. f., a plant of the genus Tripterygium of the family Celastraceae. It has a molecular formula of C20H24O6, a molecular weight of 360.4, and a structural formula shown below.

A large number of in vivo and in vitro studies have shown that triptolide has significant biological activities such as anti-tumor activity, anti-inflammatory activity, immunosuppressive activity, and anti-male fertility activity. Triptolide can significantly prolong the survival time of L615 leukemia mice, and also shows a significant therapeutic effect for human leukemia with a complete remission rate of up to 40% (18/45) [Xia Zhi-Lin et al., “Pharmacological and Clinical Studies of Triptolide.” Acta Pharmacologica Sinica, 1992, (6)427-431]. It is clinically used for the treatment of psoriasis, rheumatoid arthritis, leukemia, nephropathy, etc. Studies on the toxicity of triptolide, however, demonstrate that triptolide has high toxicity and a narrow therapeutic window, and has serious toxic side effects on the digestive system, urogenital system and hematological system, etc. Therefore, the clinical development research of triptolide is limited to some extent. Due to its unique chemical structure and biological activities, triptolide has received great interest from chemists and pharmacologists in various countries. In order to reveal the mechanism of action and structure-activity relationship of triptolide and to find its derivatives with high activity and low toxicity, several study groups have made systematic studies on triptolide and its analogues and have synthesized a series of triptolide derivatives [Zhang Fan et al., “Progress in Structure Modification of Triptolide.” Acta Pharmacologica Sinica, 2004, 39(10):857-864; and Tai Ting et al., “Advance in Pharmacokinetics of Triptolide.” Pharmaceutical and Clinical Research, 2012, 20(3):229-235]. Some of them have entered clinical trials. For example, Minnelide, a water-soluble prodrug of triptolide synthesized by scientists of the University of Minnesota, USA, can convert into triptolide both in vivo and in vitro. In some animal models, Minnelide showed good anti-cancer effect and less toxic reaction. For example, in a nude mouse model of pancreatic cancer, Minnelide prolonged the survival of mice by reducing the tumor volume and the spread of the tumor, and Minnelide showed no significant toxic effect at a dosage effective to tumor regression. Minnelide is now entering phase I clinical trials [Chugh R, et al., “A preclinical evaluation of Minnelide as a therapeutic agent against pancreatic cancer.” Sci Transl Med., 2012; 4(156):156ra139.]. Unfortunately, no triptolide or derivatives thereof has been found to enter phase II clinical trials so far. Therefore, researchers still need to make further studies in order to explore methods related to safe clinical application of triptolide as well as novel triptolide derivatives with high activity and low toxicity. In addition, the pharmacokinetic characteristics of triptolide for both oral and intravenous injection suggest that triptolide has a short elimination half-life, undergoes fast absorption, distribution, metabolism, and elimination in body, and the plasma drug concentration and tissue drug concentrations of which fluctuate greatly over time. Hence, triptolide does not have ideal pharmacokinetic properties, and are unfavorable for clinical application, and might increase the incidence of clinical adverse reactions. Thus, it is very significant to explore novel triptolide derivatives and relevant formulations with good pharmacokinetic characteristics [Tai Ting et al., “Advance in Pharmacokinetics of Triptolide.” Pharmaceutical and Clinical Research, 2012, 20(3):229-235].
Therefore, there is still a need in the market for triptolide drugs with good biological activities and pharmacokinetic characteristics and less toxicity. So far, there are still no reports on the synthesis and application of triptolide derivatives with these characteristics.